1. Field Of The Invention
Obesity represents a state of increased body fat which may decrease longevity, aggravate the onset and progression of other diseases, e.g., heart disease, diabetes, gallstones, and impace on one's social or economic status. [The Obese Patient, G. A. Bray, Vol. IX in the series "Major Problems in Internal Medicine", W. B. Saunders Co., 1976].
Hyperinsulinemia is a metabolic characteristic of all forms of human and animal obesity. Excess insulin levels not only stimulate food intake and promote lipid biosynthesis and storage, but also reduce lipid mobilization and utilization. Thus, hyperinsulinemia produces and maintains the excess fat deposition which characterizes the obese state. The hyperinsulinemia in obesity appears prior to the development of insulin resistance in tissues and may be due to abnormal regulation of insulin biosynthesis and/or secretion in the pancreas. Thus, the development of agents which reduce insulin levels will have therapeutic importance in the treatment of obesity.
This disclosure relates to the use of thromboxane synthase inhibitors as antiobesity agents and insulin lowering agents.
2. Description Of The Prior Art
A paper entitled "On the Inhibitory Potency of Imidazole and its Derivatives on Thromboxane Synthetase", Hsin-Hsiung Tai et al., Biochemical and Biophysical Research Communications 80: 236-242 (1978) discloses the finding that the relative inhibitory potency of imidazole and derivatives on thromboxane synthase from human platelets is increased by substitution of the 1-position and abolished in other positions. The potency of 1-substituted imidazoles was increased as the side chain became more hydrophobic. Among the imidazole derivatives tested, 1-nonylimidazole and 1-(2-isopropyl phenyl)-imidazole showed the highest potency with I.sub.50 in the range of 10.sup.-8 M. There was no mention, however, of the foregoing thromboxane synthase inhibitors as antiobesity agents or insulin lowering agents.
A paper entitled "Studies on the Thromboxane Synthesizing System in Human Platelet Microsomes", Hsin-Hsiung Tai et al., Biochimica et Biophysica Acta, 531: 286-294 (1978) discloses the use of N-substituted imidazoles, sulfhydryl inhibitors, prostaglandin endoperoxide analog, prostaglandin antagonist and N-0164 as thromboxane synthetase inhibitors. There was, however, no indication that said compounds could be used as antiobesity agents or insulin lowering agents.
An abstract entitled "Metyrapone, An Inhibitor of Thromboxane Synthetase and Platelet Aggregation", Hsin-Hsiung Tai et al., Fed. Proc. 38: 407 (1979), discloses metyrapone(2-methyl-1,2-di-3-pyridyl-1-propanone) as a thromboxane synthase inhibitor. No mention, however, was made of the use of said compound as an antiobesity agent or insulin lowering agent.
An abstract entitled "Synthesis and Biological Properties of Selective Inhibitors of Thromboxane Synthetase", Josef Fried et al., Abstracts, Fourth International Prostaglandin Conference, Washington, D.C., May 27-31, 1979, 37, discloses prostaglandin-like compounds and substances derived by partial synthesis form (+)- and (-)-pinene as thromboxane synthase inhibitors. The prostaglandin-like compounds showed 67% inhibition of thromboxane synthase at 50 .mu.g and the compound derived from pinene showed 50% inhibition at 10 .mu.g. Neither of these compounds, however, disclosed a utility as antiobesity agents or insulin lowering agents.
An abstract entitled "The Effect of SQ 80,338 (1-(3-Phenyl-2-Propenyl)-1H-Imidazole) on Thromboxane Synthetase Activity and Arachidonic Acid-Induced Platelet Aggregation and Bronchoconstriction", D. N. Harris et al., Abstracts, Fourth International Prostaglandin Conference, Washington, D.C., May 27-31, 1979, 46, discloses the use of the aforementioned compound as a thromboxane synthase inhibitor. There was, however, no mention of the aforesaid compound as an antiobesity agent or insulin lowering agent.
An abstract entitled "Inhibition of Dog Platelet Reactivity Following 1-Benzylimidazole Administration", R. H. Harris et al., Abstracts, Fourth International Prostaglandin Conference, Washington, D.C., May 27-31, 1979, 46, discloses the use of the aforementioned compound as a thromboxane synthase inhibitor. There was, however, no mention of said compound as an antiobesity agent or insulin lowering agent.
An abstract entitled "On the Inhibitory Potency of Pyridine and its Derivatives on Thromboxane Synthetase", Hsin-Hsiung Tai et al., Abstracts, Fourth International Prostaglandin Conference, Washington, D.C., May 27-31, 1979, 115, discloses the inhibiting effect of pyridine and its derivatives on microsomal thromboxane synthase activity from human platelets. There was, however, no indication that pyridine or its derivatives could be used as an antiobesity agent or insulin lowering agent.
An abstract entitled "Selective Inhibition of Thromboxane Synthetase by Pyridine and its Derivatives", T. Miyamoto et al., Abstracts, Fourth International Prostaglandin Conference, Washington, D.C., May 27-31, 1979, 82, discloses the inhibition by pyridine of enzymatic formation of TXB.sub.2 from PGH.sub.2 by rabbit platelet microsomes. There was, however, no mention of pyridine or it derivatives as an antiobesity agent or insulin lowering agent.
European Patent Application No. 0 000 951 discloses pharmaceutical compositions containing a 1-hydrocarbylimidazole as inhibitors of blood platelet aggregation and as antihypertensives. Specific compounds mentioned are 1-methylimidazole, 1-n-butylimidazole, 1-n-pentylimidazole, 1-n-hexylimidazole, 1-pent-2-enylimidazole, 1-pent-4-enylimidazole, 1-(3-methylbutyl)imidazole, 1-cyclohexylmethylimidazole, 1-cycloheptylimidazole and 1-cyclopentylimidazole. There is, however, no mention of any of the foregoing compounds as antiobesity agents or insulin lowering agents.
In accordance with the present invention, it has been found that selected thromboxane synthase inhibitors show a utility as antiobesity agents and insulin lowering agents.